KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy

Tawfeeq Shekh-Ahmad, Ramona Eckel, Sharadha Dayalan Naidu, Maureen Higgins, Masayuki Yamamoto, Albena Dinkova-Kostova, Stjepana Kovac, Andrey Y. Abramov (Lead / Corresponding author), Matthew C. Walker (Lead / Corresponding author)

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    Abstract

    Hippocampal sclerosis is a common acquired disease that is a major cause of drug-resistant epilepsy. A mechanism that has been proposed to lead from brain insult to hippocampal sclerosis is the excessive generation of reactive oxygen species, and consequent mitochondrial failure. Here we use a novel strategy to increase endogenous antioxidant defences using RTA 408, which we show activates nuclear factor erythroid 2-related factor 2 (Nrf2, encoded by NFE2L2) through inhibition of kelch like ECH associated protein 1 (KEAP1) through its primary sensor C151. Activation of Nrf2 with RTA 408 inhibited reactive oxygen species production, mitochondrial depolarization and cell death in an in vitro model of seizure-like activity. RTA 408 given after status epilepticus in vivo increased ATP, prevented neuronal death, and dramatically reduced (by 94%) the frequency of late spontaneous seizures for at least 4 months following status epilepticus. Thus, acute KEAP1 inhibition following status epilepticus exerts a neuroprotective and disease-modifying effect, supporting the hypothesis that reactive oxygen species generation is a key event in the development of epilepsy.

    Original languageEnglish
    Pages (from-to)1390-1403
    Number of pages14
    JournalBrain
    Volume141
    Issue number5
    Early online date12 Mar 2018
    DOIs
    Publication statusPublished - May 2018

    Keywords

    • epilepsy
    • epileptogenesis
    • mitochondrial dysfunction
    • Nrf2-KEAP1 pathway
    • oxidative stress

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    Cite this

    Shekh-Ahmad, T., Eckel, R., Dayalan Naidu, S., Higgins, M., Yamamoto, M., Dinkova-Kostova, A., Kovac, S., Abramov, A. Y., & Walker, M. C. (2018). KEAP1 inhibition is neuroprotective and suppresses the development of epilepsy. Brain, 141(5), 1390-1403. https://doi.org/10.1093/brain/awy071